Inhibiting CREB binding protein (CBP)

ABSTRACT

The present disclosure is directed to inhibitors of the CBP/p300 family of bromodomains. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of the CBP/p300 family of bromodomains. For instance, the disclosure is concerned with compounds and compositions for inhibition of the CBP/p300 family of bromodomains, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of CBP/p300 family of bromodomains, and methods of synthesis of these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/457,596, filed Jun. 28, 2019, which claims the benefit of U.S.Provisional Application No. 62/692,593, filed Jun. 29, 2018, and U.S.Provisional Application No. 62/819,490, filed Mar. 15, 2019, and thebenefit of foreign priority under 35 U.S.C. § 365(a) to InternationalApplication No. PCT/US2018/051235, filed Sep. 14, 2018, andInternational Application No. PCT/US2018/051214, filed Sep. 14, 2018,each of which is incorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure relates to novel chemical compositions for inhibitingthe CREB binding protein (CBP), useful in the treatment of treatingdiseases or disorders associated with the inhibition of CBP/p300 familyof bromodomains.

BACKGROUND

CBP/p300 are lysine acetyltransferases that catalyze the attachment ofan acetyl group to a lysine side chain of histones and other proteinsubstrates. p300 (also known as EP300 and KAT3B) is a protein withmultiple domains that bind to diverse proteins including many DNAbindingtranscription factors. The cyclic AMP-responsive element-binding protein(CREB) binding protein (CBP, also known as KAT3A) is a cellular paralogof p300. p300 and CBP share extensive sequence identity and functionalsimilarity and are often referred to as CBP/p300. CBP/p300-catalyzedacetylation of histones and other proteins is pivotal to geneactivation. Heightened p300 expression and activities have been observedin advanced human cancers such as prostate and in human primary breastcancer specimens. Chemical inhibition of CBP/p300 that possessesintrinsic acetyltransferase enzymatic activity is more feasible thanblocking transcription factors with small molecules, as discovery ofchemical inhibitors of transcription factors has proven extremelychallenging. Accordingly, there is a need for novel and potent compoundsfor inhibiting CBP/p300, useful as therapies for treating certainrelated forms of cancer.

SUMMARY

A first aspect of the present disclosure relates to compounds of Formula(I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,isomer, or tautomer thereof,

wherein:

R¹ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OR⁵, —N(R⁵)₂, or—NHR⁵;

R⁵ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo,—(CH₂)_(n)—OR⁸, —C(O)R^(8′), —C(O)OR⁸, or —C(O)NR⁸R⁹, wherein eachalkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R¹⁰;

R⁸ and R⁹ are each independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R¹⁰ or R¹¹; or

R⁸ and R⁹ may combine with the atom to which they are both attached toform a spiroheterocyclyl, heterocyclyl, or heteroaryl, wherein theformed spiroheterocyclyl, heterocyclyl,or heteroaryl is optionallysubstituted with one or more R¹⁰ or R¹¹;

R^(8′) is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R¹⁰ or R¹¹; or

R¹⁰ is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂,—OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²;

wherein any two R¹⁰ when on non-adjacent atoms, can combine to form abridging cycloalkyl or heterocyclyl;

wherein any two R¹⁰ when on adjacent atoms, can combine to form acycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).

Preferably, the compounds of Formula (I) are a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4,or 5;

each R¹⁰ is independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂,—OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —-C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,S(O)(C₁-C₆alkyl), S(O)N(C₁-C₆alkyl)₂, or —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl),wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, heteroaryl, or aryl is optionally substituted with one ormore R¹²;

wherein any two R¹⁰ when on non-adjacent atoms, can combine to form abridging cycloalkyl or heterocyclyl;

wherein any two R¹⁰ when on adjacent atoms, can combine to form acycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, —orN(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a table of compounds in accordance with various embodiments ofthe disclosure.

DETAILED DESCRIPTION

The present disclosure relates to CBP Inhibitor Compounds, definedherein as compounds having one or more of the following characteristicswhen tested according to the HTRF biochemical Assay Protocol below inExample 5: (1) a CBP IC₅₀ value of less than 1 μM; and (2) a CBP IC₅₀value of between 0.001 and 1 μM.

Compounds of the Disclosure

One aspect of the present disclosure describes compounds of Formula (I):

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof, wherein R¹ and R⁶ aredescribed above.

In some examples, the compound of Formula (I) is a stereoisomer orenantiomer of Formula (I) selected from the group consisting of Formula(I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j),(I-k), (I-l), (I-m), (I-n), (I-o) and (I-p):

A compound of Formula (I) can be a stereoisomer thereof (e.g., acompound of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g),(I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), or (I-o) wherein R₁ ismethyl and R₆ is phenyl optionally substituted with one or more) R¹⁰).

In some preferred embodiments, the compound of Formula (I) is a compoundof Formula (IV), including stereoisomers thereof:

or a pharmaceutically acceptable salt thereof, wherein n is an integerof 0, 1, 2, 3, 4, or 5 (preferably, 0, 1 or 2) and R₁₀ is as definedabove. Preferably, the compound of Formula (IV) is a compound of Formula(IV-a) (including, for example, compounds of Formula (IV-b), Formula(IV-c) or mixtures thereof), or pharmaceutically acceptable saltsthereof, wherein n is an integer of 0, 1, 2, 3, 4 or 5 (preferably 0, 1or 2) and R₁₀ is as defined above.

In certain preferred compounds of Formula (IV-a) including compounds ofFormula (IV-b) and compounds of Formula (IV-c) wherein n is 0, 1, 2, 3,4 or 5 and each R₁₀ is independently halogen or —OC₁-C₆alkyl, andwherein the —OC₁-C₆alkyl is optionally substituted with one or morehalogen. For example, in certain compounds of Formula (IV-a), n is 0, 1or 2 and each R₁₀ is independently halogen, or OC₁alkyl optionallysubstituted with one or more halogen (e.g., fluorine or chlorine). Insome compounds of Formula (IV-a), n is 2 and each R₁₀ is independentlyhalogen (e.g., fluorine or chlorine), OC₁alkyl substituted with 1, 2 or3 halogen (e.g., fluorine or chlorine), or methoxy.

Another aspect of the present disclosure is the provision ofpharmaceutical compositions comprising therapeutically effective amountsof at least one compound of Formula (I). An aspect of the presentdisclosure concerns compounds which are, or can be, inhibitors of one ormore bromodomains of the CBP/p300 family (e.g., compounds of Formula(I)).

In some embodiments, compounds of the disclosure have the Formula (I)

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,isomer, or tautomer thereof, wherein:

R¹ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OR⁵, —N(R⁵)₂, or—NHR⁵;

R⁵ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo,—(CH₂), —OR⁸, —C(O)R^(8′), —C(O)OR⁸, or —C(O)NR⁸R⁹, wherein each alkyl,cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R¹⁰;

R⁸ and R⁹ are each independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R¹⁰ or R¹¹; or

R⁸ and R⁹ may combine with the atom to which they are both attached toform a spiroheterocyclyl, heterocyclyl, or heteroaryl, wherein theformed spiroheterocyclyl, heterocyclyl,or heteroaryl is optionallysubstituted with one or more R¹⁰ or R¹¹;

R^(8′) is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R¹⁰ or R¹¹; or

R¹⁰ is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂,—OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²;

wherein any two R¹⁰ when on non-adjacent atoms, can combine to form abridging cycloalkyl or heterocyclyl;

wherein any two R¹⁰ when on adjacent atoms, can combine to form acycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, 1'S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)S 02C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).

In some embodiments, compounds of the disclosure have the Formula (I)

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,isomer, or tautomer thereof, wherein:

R¹ is —OR⁵;

R⁵ is —C₁-C₆alkyl;

R⁶ is phenyl optionally substituted with one or more R¹⁰;

R¹⁰ is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, heteroaryl, aryl, —OH, halogen, —NO₂, —CN, —NH₂,—OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²;

wherein any two R¹⁰ when on non-adjacent atoms, can combine to form abridging cycloalkyl or heterocyclyl;

wherein any two R¹⁰ when on adjacent atoms, can combine to form acycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).

In some embodiments, compounds of the disclosure have the Formula (I)

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,isomer, or tautomer thereof, wherein:

R¹ is —OR⁵;

R⁵ is —C₁-C₃alkyl;

R⁶ is phenyl optionally substituted with one or more R¹⁰;

R¹⁰ is each independently, at each occurrence halogen or —OC₁-C₆alkyl,—OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, wherein each alkyl, cycloalkyl,aryl or heteroaryl is optionally substituted with one or more —R¹²;

R¹² is halogen.

In some embodiments, compounds of the disclosure have the Formula (III):

or a pharmaceutically acceptable salt thereof, wherein,

R¹ is —OR⁵;

R⁵ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶ is —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl,aryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,or aryl is optionally substituted with one or more —R¹⁰;

R^(6′) is —H or —C₁-C₆alkyl;

R⁷ is —H, halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —S(O)₂OH, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OH, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂,—S(O)₂NH₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl) or tetrazole;

R¹⁰ is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —NHC(O)C₁-C₆alkyl,—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²;

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl);

m is an integer from 0 to 5; and

q is an integer from 0 to 4.

Multiple embodiments of the compounds of Formula (III) are providedherein. In some embodiments R¹² is halogen. In some embodiments m is 3.In some embodiments R^(6′) is H. In some embodiments R⁶ is aryl. In someembodiments R⁷ is —C(O)OH. In some embodiments R⁵ is methyl.

In some embodiments, compounds of the disclosure have the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OR⁵;

R⁵ is —C₁-C₆alkyl; and

R⁶ is phenyl optionally substituted with one or more R¹⁰;

R^(1o) is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—OC₃-C₆cyclo alkyl, —Oaryl, —Ohetero aryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—NHC(O)C₁-C₆alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²; and

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).

In some embodiments, compounds of the disclosure have the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OR⁵;

R⁵ is —C₁-C₃alkyl;

R⁶ is phenyl optionally substituted with one or more R¹⁰;

R¹⁰ is independently, at each occurrence halogen, —OC₁-C₆alkyl,—OC₃-C₆cycloalkyl, —Oaryl, or —Oheteroaryl, wherein each alkyl,cycloalkyl, aryl or heteroaryl is optionally substituted with one ormore —R¹²; and

R¹² is halogen.

In some embodiments, R⁶ is aryl optionally substituted with one or moreR¹⁰. In some embodiments, R⁶ is phenyl optionally substituted with oneor more R¹⁰.

In some embodiments R⁵ is —C₁-C₃alkyl. In some embodiments, R⁵ ismethyl.

In some embodiments, R¹⁰ is independently, at each occurrence, halogenor —OC₁-C₆alkyl, wherein —OC₁-C₆alkyl is optionally substituted withhalogen.

In some embodiments, R₁ is —OR⁵.

In some embodiments, R¹ is —OR⁵, —N(R⁵)₂, —NHR⁵, or —C₁-C₆alkyl. In someembodiments, R¹ is —OR⁵. In some embodiments, R¹ is —OR⁵ or —C₁-C₆alkyl.In some embodiments, R⁵ of R¹ is —C₁-C₆alkyl. In some embodiments, R¹ is—OR⁵; and R⁵ is —C₁-C₆alkyl. In some embodiments R¹ is —OCH₃. In someembodiments, R¹ is —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, or aryl. In someembodiments, R¹ is —C₁-C₆alkyl. In some embodiments, R¹ is methyl, ethylor propyl. In some embodiments, R¹ is methyl. In some embodiments, R¹ is—C₂-C₆alkenyl. In some embodiments, R¹ is aryl.

In some embodiments, R⁵ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, heterocyclyl,aryl, or heteroaryl. In some embodiments, R⁵ is —C₁-C₆alkyl. In someembodiments, R⁵ is —C₁-C₃alkyl. In some embodiments, R⁵ is methyl. Insome embodiments, R⁵ is ethyl.

In some embodiments, R⁶ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, or aryl. In some embodiments, R⁶ is—C₁-C₆alkyl optionally substituted with one or more R¹⁰. In someembodiments, R⁶ is aryl optionally substituted with one or more R¹⁰. Insome embodiments, R⁶ is heteroaryl optionally substituted with one ormore R¹⁰. In some embodiments, R⁶ is —C(O)OH. In some embodiments, R⁶ ishalogen. In some embodiments, R⁶ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl,spiroheterocyclyl, heteroaryl, halogen, oxo, (CH₂)_(n)—OR⁸, —C(O)R^(8′),—C(O)OR⁸, or —C(O)NR⁸R⁹, wherein each alkyl, cycloalkyl, heterocyclyl,spirocycloalkyl, spiroheterocyclyl, heteroaryl, or aryl is optionallysubstituted with one or more R¹⁰.

In some embodiments, R⁸ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, aryl, heteroaryl,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R¹⁰ or R¹¹. In some embodiments, R⁸ is H. In some embodiments, R⁸is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, oraryl, wherein R⁸ is optionally substituted with R¹⁰ or R¹¹. In someembodiments, R⁸ is —C₁-C₆alkyl optionally substituted with one or moreR¹⁰ or R¹¹. In some embodiments, R⁸ is aryl optionally substituted withone or more R¹⁰ or R¹¹. In some embodiments, R⁸ is heteroaryl optionallysubstituted with one or more R¹⁰ or R¹¹.

In some embodiments, R^(8′) is —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, aryl,heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R¹⁰ or R¹¹. In some embodiments, R^(8′) is—C₁-C₆alkyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, oraryl, wherein R^(8′) is optionally substituted with R¹⁰ or R¹¹. In someembodiments, R^(8′) is —C₁-C₆alkyl optionally substituted with one ormore R¹⁰ or R¹¹. In some embodiments, R^(8′) is aryl optionallysubstituted with one or more R¹⁰ or R¹¹. In some embodiments, R^(8′) isheteroaryl optionally substituted with one or more R¹⁰ or R¹¹.

In some embodiments, R⁹ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, aryl, heteroaryl,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R¹⁰ or R¹¹. In some embodiments, R⁹ is —H. In some embodiments, R⁹is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, oraryl, wherein R⁹ is optionally substituted with R¹⁰ or R¹¹. In someembodiments, R⁹ is —C₁-C₆alkyl optionally substituted with one or moreR¹⁰ or R¹¹. In some embodiments, R⁹ is aryl optionally substituted withone or more R¹⁰ or R¹¹. In some embodiments, R⁹ is heteroaryl optionallysubstituted with one or more R¹⁰ or R¹¹.

In some embodiments, R¹⁰ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl,—OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹². In some embodiments, R¹⁰is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl, wherein R¹⁰ issubstituted with R¹². In some embodiments, R¹⁰ is halogen. In someembodiments, R¹⁰ is each independently, at each occurrence, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl,heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂,—OC₁-C₆alkyl, —OC₃-C₆cyclo alkyl, Oaryl, Oheteroaryl, —NHC₁-C₆alkyl,—N(C₁ -C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²; wherein any two R¹⁰ whenon non-adjacent atoms, can combine to form a bridging cycloalkyl orheterocyclyl; wherein any two R¹⁰ when on adjacent atoms, can combine toform a cycloalkyl, heterocyclyl, aryl or heteroaryl. In someembodiments, R¹⁰ is each independently, at each occurrence halogen or—OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl, wherein eachalkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with oneor more —R¹².

In some embodiments, R¹¹ is —C₁-C₆alkyl, —-C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl,—OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁ -C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹². In some embodiments, R¹¹is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl, wherein R¹¹ issubstituted with R¹². In some embodiments, R¹¹ is halogen.

In some embodiments, R¹² is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl,—OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl, —N(C₁-C₆alkyl)S 02C 1-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl). In some embodiments, R¹² is —H. In someembodiments, R¹² is halogen.

In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3. In some embodiments, n is 4.

In some embodiments, R¹ is —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocycloalkyl, heteroaryl, oraryl.

Preferably, the compound is a CBP Inhibitor Compound of Formula (I)wherein R₁ is —OCH₃. In some embodiments, a CBO Inhibitor Compound ofFormula (I) includes R₁ is —OCH₃ and R₆ is C₆ aryl (phenyl) optionallysubstituted with one or more R₁₀. In some embodiments, a CBO InhibitorCompound of Formula (I) includes R₁ is —OCH₃ and R₆ is C₆ aryl (phenyl)optionally substituted with one or more R₁₀ being selected from thegroup consisting of halogen (e.g., fluorine) and methoxy, wherein themethoxy is optionally substituted with one or more R₁₂. In someembodiments, a CBO Inhibitor Compound of Formula (I) includes R₁ is—OCH₃ and R₆ is C₆ aryl (phenyl) optionally substituted with one or moreR₁₀ being selected from the group consisting of halogen (e.g., fluorine)and methoxy, wherein the methoxy is optionally substituted with one ormore R₁₂ and R₁₂ is a halogen (preferably, fluorine).

In some embodiments, a compound of the disclosure is a compound selectedfrom FIG. 1, or a pharmaceutically acceptable salt thereof.

Method of Synthesizing the Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the examples given below.

The compounds of the present disclosure, i.e., compounds of Formula (I),or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, may be prepared by methods knownin the art of organic synthesis as set forth in part by the followingsynthetic schemes. In the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles or chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Third edition, Wiley, New York 1999). These groupsare removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection processes, as well as the reaction conditions and order oftheir execution, shall be consistent with the preparation of compoundsof Formula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

The disclosure also includes pharmaceutical compositions comprising oneor more CBP Inhibitor Compounds as described herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In some embodiments, pharmaceutical compositionsreported herein can be provided in a unit dosage form (e.g., capsule,tablet or the like). Pharmaceutical compositions comprising a compoundof Formula (I) can be provided in an oral dosage form such as a capsuleor tablet. The oral dosage form optionally comprises one or morefillers, disintigrants, lubricants, glidants, anti-adherents and/oranti-statics. In some embodiments, an oral dosage form is prepared viadry blending. In some embodiments, an oral dosage form is a tablet andis prepared via dry granulation. For example, a CBP Inhibitor compoundof the present disclosure can be dosed at 1 mg to 1 g at atherapeutically effective frequency.The pharmaceutical compositions maybe orally administered in any orally acceptable dosage form.Accordingly, a patient and/or subject can be selected for treatmentusing a compound described herein by first evaluating the patient and/orsubject to determine whether the subject is in need of inhibition ofCBP, and if the subject is determined to be in need of inhibition ofCBP, then administering to the subject a composition described herein.

A pharmaceutical composition can comprise one or more compounds ofFormula (I) including any compound disclosed in the examples below, asprovided herein. In one example, an active pharmaceutical ingredient(API) can comprise about 90% or more of a compound of Formula (I) and upto about 10% (preferably up to about 5%, most preferably up to about2.5% including about 1.5%) of the compound of Formula (I). Oral dosageforms comprising a compound of Formula (I) can be prepared as adrug-in-capsule (DiC), encapsulated simple dry-blend granulation, andlipid-based solution in hard shell capsule. The capsules can containpharmaceutically acceptable excipients, and encapsulated capsules can bepackaged in high-density polyethylene induction sealed bottles.

EXAMPLES Definitions Used in the Following Schemes and Elsewhere Hereinare

-   ACN acetonitrile-   Ac₂O acetic anhydride-   (±)BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalen-   Boc tert-butoxycarbonyl-   n-BuOH butanol-   cm centimeter-   DCE 1,2-dichloroethane-   DCM dichloromethane or methylene chloride-   DEA diethylamine-   DMC 2-Chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride-   DMP Dess-Martin periodinane-   DMTMM 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium    chloride-   DIEA N,N-diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   dppf bis(diphenylphosphino)ferrocene-   ES electrospray ionization-   Et₃N triethylamine-   EtOAc ethyl acetate-   EtOH ethanol-   FA formic acid-   FCC flash column chromatography-   h hours-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HCl hydrogen chloride-   HOAc acetic acid-   HPLC high performance liquid chromatography-   (i-Pr)₂NEt N,N-diisopropylethylamine-   L liter-   LC/MS liquid chromatography/mass spectrometry-   LDA lithium diisopropylamine-   K₂CO₃ potassium carbonate-   MeOH methanol-   mL milliliter-   mmol millimole-   mg milligram-   MHz megahertz-   MS mass spectrometry-   m/z mass/charge ratio-   NB S N-bromosuccinimide-   nm nanometer-   NMM 4-methylmorpholine-   NMR nuclear magnetic resonance-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium-   Ph₃P triphenylphosphine-   PhCHO benzaldehyde-   PhMe toluene-   ppm parts per million-   rt room temperature-   RT rentention time-   SFC supercritical fluid chromatography-   STAB sodium triacetoxyborohydride-   p-TSA para-toluenesulfonic anhydride-   p-TsOH para-toluenesulfonic acid-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   UV ultraviolet-   XPhos 2-dic yclohexylpho sphino-2′,4′,6′-triisopropylbiphenyl

Materials

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisturesensitive reagents wereperformed under a nitrogen atmosphere and all reactions utilizingmicrowave irraditation were run on a Biotage Initiator EXP EUinstrument.

Unless otherwise noted, mass-triggered HPLC purification and/or purityand low resolution mass spectral data were measured using either: (1)Waters Acquity ultra performance liquid chromatography (UPLC) system(Waters Acquity UPLC with Sample Organizer and Waters Micromass ZQ MassSpectrometer) with UV detection at 220 nm and a low resonanceelectrospray positive ion mode (ESI) (Column: Acquity UPLC BEH C18 1.7μm 2.1×50 mm; gradient: 5-100% Solvent B (95/5/0.09%:Acetonitrile/Water/Formic Acid) in Solvent A (95/5/0.1%: 10 mM AmmoniumFormate/Acetonitrile/Formic Acid) for 2.2 min then 100-5% Solvent B inSolvent A for 0.01 min then hold at 5% Solvent B in Solvent A for 0.29min) or (2) Waters HT2790 Alliance high performance liquidchromatography (HPLC) system (Waters 996 PDA and Waters ZQ Single QuadMass Spectrometer) with UV detection at 220 nm and 254 nm and a lowresonance electrospray ionization (positive/negative) mode (ESI)(Column: XBridge Phenyl or C18, 5 μm 4.6×50 mm; gradient: 5-95% SolventB (95% methanol/5% water with 0.1% Formic Acid) in Solvent A (95%water/5% methanol with 0.1% Formic Acid) for 2.5 min then hold at 95%Solvent B in Solvent A for 1 min (purity and low resolution MS only).

General Methods of Compound Preparation

Described herein are methods of synthesizing the compounds of thepresent disclosure. Compounds of the present disclosure can besynthesized according to the synthetic schemes provided below.Preparation of the starting material for Schemes 1 and 2 (“Intermediate1”) is described below. Preparation of the starting material for Schemes3 and 4 can be found in Example 1, Part A of U.S. Pat. No. 4,404,207.

Unless otherwise specified, the substituents R² and R³ in the followingreaction schemes are defined as follows, and R⁶ is as defined in thedescription and claims.

Scheme 1 provides methods useful for synthesizing compounds of FormulaI.

Scheme 2 provides methods useful for synthesizing compounds of FormulaI.

Alternatively, Scheme 3 provides methods useful for synthesizing certaincompounds of Formula I.

Alternatively, Scheme 4 provides methods useful for synthesizing certaincompounds of Formula I.

Preparation of Intermediate 1: methyl(S)-5-amino-6-bromo-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Step 1. 8-chloro-5-methoxy-2-methylquinoline Hydrochloride

Into a 5 L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, 2-chloro-5-methoxyaniline (250 g, 1.59mol) was dissolved in 1-butanol (1200 mL). Then hydrochloric acid (aq,36.5%, 526.5 mL) and chloranil (456.5 g, 1.86 mol) were added. Theresulting mixture was stirred for 1 h at 100° C. under nitrogenatmosphere. Then a solution of (E)-but-2-enal (169 mL, 2.06 mol) in1-butanol (300 mL) was added dropwise. The resulting solution wasstirred for 1 h at 100° C. under nitrogen atmosphere. The oil bath wascooled to 70° C. and tetrahydrofuran (1500 mL) was added. Then theresulting mixture was stirred for 1 h at 70° C. The reaction mixture wascooled to 0° C. and the solids were filtered. The solids were washedwith tetrahydrofuran (3 L) at 0° C. This afforded the title compound(300 g, 77%) as a yellow solid. MS: (ES, m/z): 208, 210 [M+H]⁺. thendried in an oven to afford 8-chloro-5-methoxy-2-methylquinolinehydrochloride (83.0 g, 74%) as a yellow solid. MS (ES, m/z): 208 [M+H]⁺.

Step 2. 5-methoxy-2-methylquinoline

Into a 1000-mL 3-necked round-bottom flask,8-chloro-5-methoxy-2-methylquinoline hydrochloride (50 g, 204.82 mmol)was dissolved in methanol (300 mL). Then sodium hydroxide (3M, 205 mL)and 10% palladium on carbon (25 g) were added. Hydrogen (g) was chargedinto the reaction mixture. The reaction mixture was stirred under ahydrogen atmosphere for 3 h at room temperature. The reaction was ventedto nitrogen and the solids were filtered out over celite. The filteredsolution was concentrated under vacuum. The residue was subjected topurification by FCC eluting with ethyl acetate/petroleum ether (1:5).This afforded the title compound (28.5 g, 80%) as a yellow oil. MS: (ES,m/z): 174 [M+H]⁺.

Step 3. (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

Into a 30-mL pressure tank reactor (50 atm), 5-methoxy-2-methylquinoline(4.0 g, 23.09 mmol) was dissolved in methanol (10 mL). ThenRu(OTf)(η6-hexamethylbenzene)((S,S)-TsDPEN)([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium, prepared according to the procedure in J. Am.Chem. Soc. 2011, 133, 9878-9891) (150 mg, 0.23 mmol) was added. To theabove hydrogen was introduced in. The resulting solution was stirred for6 h at room temperature. The resulting mixture was concentrated undervacuum. The residue was subjected to purification by FCC eluting withethyl acetate/petroleum ether (1:4). This afforded the title compound(3.0 g, 73%) as a yellow oil. MS: (ES, m/z): 178 [M+H]⁺.

Step 4. methyl(S)-5-methoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Into a 250-mL round-bottom flask,(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (18 g, 99.52 mmol)was dissolved in dichloromethane (100 mL). Then pyridine (23.6 g, 298.36mmol) was added, followed by methyl carbonochloridate (9.4 g, 99.47mmol). The resulting solution was stirred for 1 h at room temperature.The resulting solution was diluted with 100 mL of dichloromethane andwashed with 3×200 mL of water. The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was subjected to purification by FCC eluting with ethylacetate/petroleum ether (1:3). This afforded the title compound (21 g,89%) as a yellow oil. MS: (ES, m/z): 236 [M+H]⁺.

Step 5. methyl(S)-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Into a 500-mL 3-necked round-bottom flask, methyl(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (21 g,89.36 mmol) was dissolved in dichloromethane (150 mL). Then borontribromide (150 mL, 0.15 mol, 1 M in CH₂Cl₂) was added. The resultingsolution was stirred for 1 h at room temperature. The reaction was thenquenched by the addition of 300 mL of water. The resulting mixture wasextracted with 3×300 mL of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was subjected to purification by FCC elutingwith ethyl acetate/petroleum ether (1:2). This afforded the titlecompound (13.5 g, 68%) as a yellow solid. MS: (ES, m/z): 222 [M+H]⁺.

Step 6. methyl(S)-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroquinoline-1(2H)-carboxylate

Into a 250-mL round-bottom flask, methyl(2S)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (5 g,18.08 mmol) was dissolved in dichloromethane (50 mL). Then pyridine(14.3 g, 180.78 mmol) and trifluoromethanesulfonic anhydride (10.2 g,36.15 mmol) were added. The resulting solution was stirred for 1 h atroom temperature. The resulting mixture was washed with 3×100 mL ofwater. The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue wassubjected to purification by FCC eluting with ethyl acetate/petroleumether (1:3). This afforded the title compound (5.5 g, 86%) as a yellowoil. MS: (ES, m/z): 354 [M+H]⁺.

Step 7. methyl(S)-5-((diphenylmethylene)amino)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, methyl(2S)-2-methyl-5-[(trifluoromethane)sulfonyloxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate(23.5 g, 65.18 mmol) was dissolved in toluene (100 mL). Thendiphenylmethanimine (17.9 g, 97.78 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (1.19 g, 1.30mmol), (+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (2.43 g, 3.90mmol) and cesium carbonate (42.4 g, 130.13 mmol) were added. Theresulting solution was stirred overnight at 100° C. under nitrogenatmosphere. The reaction mixture was cooled and the solids were filteredout. The residue was subjected to purification by FCC eluting with ethylacetate/petroleum ether (1:3). This afforded the title compound (33 g,80%) as a yellow oil. MS: (ES, m/z): 385 [M+H]⁺.

Step 8. methyl(S)-5-amino-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Into a 500-mL round-bottom flask, methyl(2S)-5-[(diphenylmethylidene)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(33 g, 85.93 mmol) was dissolved in methanol (200 mL). Then sodiumacetate (17 g, 207.23 mmol) and hydroxylamine hydrochloride (12.3 g,177.00 mmol) were added. The resulting solution was stirred for 2 h atroom temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was subjected to purificationby FCC eluting with ethyl acetate/petroleum ether (1:2). This affordedthe title compound (12.5 g, 66%) as a yellow solid. MS: (ES, m/z): 221[M+H]⁺.

Step 9. methyl(S)-5-amino-6-bromo-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(Intermediate 1)

Into a 100-mL 3-necked round-bottom flask, methyl(2S)-5-amino-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (1 g,4.09 mmol) was dissolved in acetonitrile (20 mL). ThenN-bromosuccinimide (730 mg, 4.10 mmol) was added. The resulting solutionwas stirred for 30 min at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was subjected to purification byFCC eluting with ethyl acetate/petroleum ether (1:1). This afforded thetitle compound (1.1 g, 90%) as a yellow solid. MS: (ES, m/z): 299, 301[M+H]⁺.

H-NMR: (400 MHz, CD3OD, ppm): 7.19 (d, J=8.8 Hz, 1H), 6.84(d, J=8.8 Hz,1H), 4.73-4.69(m, 1H), 3.74(s, 3H), 2.64-2.57(m, 1H), 2.55-2.44(m, 1H),2.12-2.05(m, 1H), 1.82-1.79(m, 1H), 1.17(d, J=6.9 Hz, 3H).

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The synthetic schemes are presented for the synthesis of certaincompounds herein disclosed. The process and results for the assaystesting BET family bromodomain inhibition and effects on a cancer cellline proliferation are also described.

Example 1: methyl(S)-2-(2-(1H-pyrazol-1-ypethyl)-7-methyl-3-(2-(01-methyl-1H-pyrazol-3-yl)methypamino)ethyl)-3,7,8,9-tetrahydro-6H-imidazo[4,5-f]quinoline-6-carboxylate

Step 1. 6-fluoro-2-methyl-5-nitroquinoline

A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO₃(19.6 mL, 0.437 mol) was stirred for 20 min at 0° C. This was followedby the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) indichloromethane (300 mL) at 0° C. The resulting mixture was stirred for15 hours at room temperature (25° C.). The reaction mixture was dilutedwith water (300 mL). The pH value of the solution was adjusted to 8 withsodium bicarbonate (saturated aqueous solution). The resulting solutionwas extracted with dichloromethane (3×300 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:4 ethyl acetate/petroleum ether) toafford 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0g, 94%). LCMS (ES, m/z): 207 [M+H]⁺.

Step 2. (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol),chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) intoluene (100 mL) was stirred for 30 min at room temperature (25° C.)under an atmosphere of nitrogen. This was followed by the addition of I₂(410 mg, 1.62 mmol), and 6-fluoro-2-methyl-5-nitroquinoline (33.0 g,0.160 mol) in toluene (100 mL). The resulting mixture was stirred for 20h at room temperature (25° C.) under hydrogen (50 atm). The resultingmixture was concentrated under vacuum and purified by silica gelchromatography (eluting with 1:1 ethyl acetate/petroleum ether) toafford the crude product (35.0 g). The crude product was dissolved inethyl acetate (230 mL), followed by the addition of D-Camphorsulfonicacid (36.9 g, 0.158 mol). The resulting solution was stirred for 1 h at60° C. and then cooled to room temperature. The solids were collected byfiltration, and rinsed with ethyl acetate (120 mL). The solids weredissolved in water (50 mL). The pH value of the solution was adjusted to8 with sodium bicarbonate (saturated aqueous solution). The resultingsolution was extracted with ethyl acetate (3×120 mL). The combinedorganic layers was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to afford(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a redsolid (25.5 g, 76%). LCMS (ES, m/z): 211 [M+H]⁺.

Step 3. methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline(25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), and methylcarbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) wasstirred for 3 h at room temperature (25° C.). The reaction was washedwith 1N hydrogen chloride (aq., 2×70 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to afford methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a yellow solid (29.8 g, 92%). LCMS (ES, m/z): 269 [M+H]⁺.

Step 4. methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate(30.5 g, 0.220 mol), and methyl (1R,3R)-3-aminocyclohexane-1-carboxylate(25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred for 15 h at 90° C.and then cooled to room temperature. The reaction was quenched by theaddition of water (200 mL) and extracted with ethyl acetate (3×300 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydro quinoline-1-carboxylate as a red oil (32 g, 72%).LCMS (ES, m/z): 406 [M+H]⁺.

Step 5. methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-2-methyl-5-nitro-6-[[(1R,3R)-4-(methoxycarbonyl)cyclohexyl]amino]-1,2,3,4-tetrahydroquinoline-1-carboxylate(31.0 g, 76.46 mmol), NH₄Cl (24.3 g, 454.28 mmol), and Fe (powder, 64.3g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL), water (100mL) was stirred for 1 h at 80° C. and then cooled to room temperature.The solids were filtered out by filtration. The resulting solution wasdiluted with water (300 mL) and extracted with ethyl acetate (3×400 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to afford methyl(2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas a dark green solid (27.5 g, 92%). LCMS (ES, m/z): 376 [M+H]³⁰ .

Step 6. methyl(2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of 2-(4-chlorophenyl)-2-hydroxyacetic acid (112 mg, 0.60mmol), HATU (304 mg, 0.80 mmol), methyl(2S)-5-amino-6[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(150 mg, 0.40 mmol), and DIEA (155 mg, 1.20 mmol) inN,N-dimethylformamide (2 mL) was stirred for 15 h at room temperature(25° C.). The resulting solution was diluted with water (30 mL), andextracted with ethyl acetate (3×50 mL). The organic layers were combinedand washed with brine (2×25 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The resulting crude product was purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to afford methyl(2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas yellow oil (70.0 mg, 32%). LCMS (ES, m/z): 544 [M+H]⁺.

Step 7. methyl(7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

A solution of methyl(2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(60.0 mg, 0.11 mmol) in AcOH (2 mL) was stirred for 15 h at 40° C. andthen cooled to room temperature. The reaction mixture was diluted withwater (10 mL). The pH value of the solution was adjusted to 8 withsodium bicarbonate (saturated aqueous solution). The resulting solutionwas extracted with ethyl acetate (3×15 mL). The organic layers werecombined and dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The resulting crude product was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford methyl(7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylateas yellow oil (46.0 mg, 79%). LCMS (ES, m/z): 526 [M+H]⁺.

Step 8.(1R,3R)-3-[(7S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid(PH-FMA-PJ00136-1145-0A);(1R,3R)-3-[(7S)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (PH-FMA-PJ00136-1145-0B)

A solution of methyl(7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (50.0 mg, 0.10 mmol), and LiOH (11.4 mg,0.48 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred for 15h at 25° C. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBDColumn, 5 um, 19×150 mm; Mobile Phase, A: water (containing 10 mmol/LNH₄HCO₃) and B: ACN (10% to 37% over 12 min); Detector: UV 254 nm). Theproduct fractions were lyophilized to afford(1R,3R)-3-[(7S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (413) as a white solid (10.5 mg, 43%); and(1R,3R)-3-[(7S)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (501) as a white solid (7.0 mg, 29%).

First eluting isomer (413): ¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 7.49 (d,J=9.0 Hz, 1H), 7.42-7.33 (m, 5H), 6.19 (s, 1H), 4.92-4.90 (m, 1H),4.82-4.72 (m, 1H), 3.79 (s, 3H), 3.34-3.20 (m, 1H), 3.02-2.94 (m, 1H),2.90-2.87 (m, 1H), 2.36-2.09 (m, 4H), 1.99-1.96 (m, 1H), 1.80-1.42 (m,5H), 1.16 (d, J=6.6 Hz, 3H). LCMS (ES, m/z): 512 [M+H]⁺.Second eluting isomer (501): ¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 7.52-7.33(m, 6H), 6.22 (s, 1H), 4.84-4.73 (m, 2H), 3.78 (s, 3H), 3.27-3.16 (m,1H), 3.04-2.92 (m, 1H), 2.90-2.88 (m, 1H), 2.46-2.35 (m, 2H), 2.30-2.22(m, 1H), 2.15-2.02 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.55 (m, 2H),1.40-1.28 (m, 1H), 1.15 (d, J=6.6 Hz, 4H). LCMS (ES, m/z): 512 [M+H]⁺.

The compounds listed in FIG. 1 were prepared using standard chemicalmanipulations and procedures similar to those described herein. In FIG.1, “Eluted Isomer” refers to the order in which the compound eluted bypreparative HPLC.

Example 2: Compounds 424 and 660:(1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (424);(1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (660)

Step 1. 2-(5-fluoro-2-methoxyphenyl)-2-ktrimethylsilyl)oxylacetonitrile

A solution of ZnI₂ (1.6 mg, 0.01 mmol), 5-fluoro-2-methoxybenzaldehyde(1.54 g, 9.99 mmol) in trimethylsilanecarbonitrile (1.5 mL, 11.25 mmol)was stirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. The resulting crude product was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford2-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile as awhite solid (2.0 g, 79%).

Step 2. 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic Acid

A solution of2-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile (1.50g, 5.92 mmol) in hydrochloric acid (10 mL, 12M) was stirred for 1 h at25° C., and then stirred for 2 h at 70° C. The reaction mixture wascooled and concentrated under vacuum. The crude product was purified byreverse phase chromatography (Column: C18; Mobile phase, A: water(containing 0.05% TFA) and B: ACN (5% to 20% over 30 min); Detector, UV254 nm) to afford 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid as awhite solid (1.10 g, 93%).

Step 3. 6-fluoro-2-methyl-5-nitroquinoline

A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO₃(19.6 mL, 0.437 mol) was stirred for 20 min at 0° C. This was followedby the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) indichloromethane (300 mL) at 0° C. The resulting mixture was stirred for15 h at room temperature (25° C.). The reaction mixture was diluted withwater (300 mL). The pH value of the solution was adjusted to 8 withsodium bicarbonate (saturated aqueous solution). The resulting solutionwas extracted with dichloromethane (3×300 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:4 ethyl acetate/petroleum ether) toafford 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0g, 94%). LCMS (ES, m/z): 207 [M+H]⁺.

Step 4. (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol),chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) intoluene (100 mL) was stirred for 30 min at room temperature (25° C.)under an atmosphere of nitrogen. This was followed by the addition of I₂(410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160mol) in toluene (100 mL). The resulting mixture was stirred for 20 h atroom temperature (25° C.) under hydrogen (50 atm). The resulting mixturewas concentrated under vacuum and purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to afford the crudeproduct (35.0 g). The crude product was dissolved in ethyl acetate (230mL), followed by the addition of D-Camphorsulfonic acid (36.9 g, 0.158mol). The resulting solution was stirred for 1 h at 60° C. and thencooled to room temperature. The solids were collected by filtration, andrinsed with ethyl acetate (120 mL). The solids were dissolved in water(50 mL). The pH value of the solution was adjusted to 8 with sodiumbicarbonate (saturated aqueous solution). The resulting solution wasextracted with ethyl acetate (3×120 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to afford(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a redsolid (25.5 g, 76%). LCMS (ES, m/z): 211 [M+H]⁺.

Step 5. methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline(25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), methylcarbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) wasstirred for 3 h at room temperature (25° C.). The reaction was washedwith 1M hydrochloric acid (2×70 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to afford methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a yellow solid (29.8 g, 92%). LCMS (ES, m/z): 269 [M+H]⁺.

Step 6. methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate(30.5 g, 0.220 mol), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate(25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred for 15 h at 90° C.and then cooled to room temperature. The reaction was quenched by theaddition of water (200 mL) and extracted with ethyl acetate (3×300 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a red oil (32 g, 72%). LCMS (ES, m/z): 406 [M+H]⁺.

Step 7. methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(31.0 g, 76.46 mmol), NH₄Cl (24.3 g, 454.28 mmol), Fe (64.3 g, 1.15 mol)in tetrahydrofuran (300 mL), ethanol (300 mL), and water (100 mL) wasstirred for 1 h at 80° C. and then cooled to room temperature. Thesolids were filtered out by filtration. The resulting solution wasdiluted with water (300 mL) and extracted with ethyl acetate (3×400 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to afford methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas a dark green solid (27.5 g, 92%). LCMS (ES, m/z): 376 [M+H]⁺.

Step 8. methyl(2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid (240 mg,1.20 mmol), HATU (228 mg, 0.60 mmol), methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(150 mg, 0.40 mmol), DIEA (0.19 mL, 1.20 mmol) in N,N-dimethylformamide(10 mL) was stirred for 1 h at 25° C. The resulting solution was dilutedwith H₂O (10 mL). The resulting solution was extracted with ethylacetate (3×15 mL) and the organic layers combined. The resulting mixturewas washed with brine (2×20 mL). The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The resulting crudeproduct was purified by silica gel chromatography (eluting with 3:2ethyl acetate/petroleum ether) to afford methyl(2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetra-hydroquinoline-1-carboxylateas a yellow solid (180 mg, 81%). LCMS (ES, m/z): 558 [M+H]⁺.

Step 9. methyl(7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-1]quinoline-6-carboxylate.

A solution of methyl(2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(180 mg, 0.32 mmol) in AcOH (8 mL) was stirred for overnight at 60° C.The reaction mixture was cooled and concentrated under vacuum. Theresulting crude product was purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to afford methyl(7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylateas a yellow solid (120 mg, 69%). LCMS (ES, m/z): 540 [M+H]⁺.

Step 10.(1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid;(1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicAcid

A solution of methyl(7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo [4,5-f]quinoline-6-carboxylate (120 mg, 0.22 mmol), andLiOH (16 mg, 0.67 mmol) in tetrahydrofuran (2.0 mL), methanol (2.0 mL)and water (2.0 mL) was stirred overnight at 25° C. The resulting mixturewas concentrated under vacuum. The crude product was purified byPrep-HPLC (Column, XBridge Prep C18 OBD Column, 19×150 mm, 5 um; Mobilephase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (15.0% to29.0% over 14 min); Detector, UV 220/254 nm). The product was separatedby Chiral-Prep-HPLC (Column, CHIRALPAK IE, 2×25 cm, 5 um; Mobile phase,A: Hex (containing 0.1% FA) and B: ethanol (hold 50.0% ethanol over 12min); Detector, UV 220/254 nm). The product fractions were concentratedto afford(1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid as a white solid(23.6 mg, 20%); and(1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid as a white solid (23.8 mg, 20%). Stereoisomeric purity wasdetermined via HPLC: Column: CHIRALPAK IE-3, Column size: 0.46×5 cm; 3μm; Mobile phase: Hex (0.1% FA) : EtOH=50:50, Flow: 1.0 ml/min.

First eluting isomer (424): 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.56-7.47(m, 1H), 7.47-7.31 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 2H),6.53(s, 1H), 4.81-4.61(m, 2H), 3.85(s, 3H), 3.78(s, 3H), 3.31-3.18(m,1H), 3.06-2.82 (m, 2H), 2.57-2.41 (m, 1H), 2.41-2.31 (m, 1H), 2.31-2.09(m, 3H), 1.83-1.58 (m, 3H), 1.49-1.21 (m, 2H), 1.16 (d, J=6.8 Hz, 3H).LCMS (ES, m/z): 526 [M+H]+.Second eluting isomer (660): 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.69-7.44(m, 2H), 7.44-7.29 (m, 1H), 7.12-6.99 (m, 1H), 6.98-6.82 (m, 1H),6.37(s, 1H), 5.03-4.91(m, 1H), 4.81-4.69(m, 1H), 3.78(s, 3H), 3.61(s,3H), 3.22-3.04(m, 1H), 3.02-2.87 (m, 2H), 2.54-2.41 (m, 1H), 2.41-2.27(m, 1H), 2.27-2.08 (m, 3H), 1.82-1.58 (m, 3H), 1.58-1.41 (m, 2H), 1.14(d, J=6.4 Hz, 3H). LCMS (ES, m/z): 526 [M+H]+.

In a preferred embodiment the disclosure provides the first elutingisomer obtained from Step 10 of the process described in Example 2above, or a pharmaceutically acceptable salt thereof. In a preferredembodiment the disclosure provides compound 424 having the followingstructure:

or a pharmaceutically acceptable salt, hydrate, solvate, or tautomerthereof.

In some embodiments, the disclosure provides a pharmaceuticalcomposition comprising compound 424 of the foregoing structure or apharmaceutically acceptable salt thereof, at a purity of at least 90%,for example greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% relative to one or more of its related stereoisomers. For example,the disclosure provides the compound 424 of the foregoing structure or apharmaceutically acceptable salt thereof, at a purity of at least 90%,e.g. greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%purity relative to compound 660 and optionally other stereoisomers ofcompound 424 depicted below. In some embodiments, the disclosureprovides a pharmaceutical composition comprising compound 424 of theforegoing structure or a pharmaceutically acceptable salt thereof, at apurity of at least 95%.

A composition of Formula (I) can comprise a compound of one or more ofFormula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i),(I-j), (I-k), (I-l), (I-m), (I-n), and/or (I-o). For example, in someembodiments the disclosure provides a composition comprising compound424 of the foregoing structure or a pharmaceutically acceptable saltthereof at a purity of at least 90% wherein the composition comprisesless than 10%, e.g. less than 9%, less than 8%, less than 7%, less than6%, less than 5%, less than 4%, less than 3%, less than 2% or less than1%, collectively of one or more of the following stereoisomers ofcompound 424, represented as Formulae (II-a)-(II-o) below:

In any of the foregoing embodiments, the percentage purity recited maybe determined by HPLC. In some embodiments the percentage purity isdetermined using the following HPLC method:

-   -   Sample Preparation:    -   Prepare 0.2 mg/mL in 70/30 Water/Acetonitrile.    -   LCMS Information:    -   Instruments:    -   MS: Waters QDa MS    -   HPLC: waters Alliance e2695    -   UV: Waters 2998 PDA    -   Conditions:    -   Mobile Phase A: 10 mM Ammonium acetate    -   Mobile Phase B: Acetonitrile    -   Column: Waters XSelect Phenyl-Hexyl, 3.5 μm, 4.6×150 mm    -   Column temperature: 35° C.    -   LC: Gradients:    -   Runtime: 25 min    -   LC Flow Rate: 1 mL/min    -   UV Wavelength: 238 nm    -   Ionization Mode: Electospray Inonization+ive    -   Injection Volume: 8 μL

For instance, the disclosure provides a pharmaceutical compositioncomprising compound 424 or a pharmaceutically acceptable salt thereof ata purity of at least 95% as determined by the above HPLC method. Thedisclosure also provides a pharmaceutical composition comprisingcompound 424 at a purity of at least 95% as determined by the above HPLCmethod.

The disclosure provides a compound of Formula II obtained by theforegoing method exemplified in Example 2:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,isomer or tautomer thereof.

It will be apparent to the skilled reader that each of the stereoisomersof the compound of Formula (II) can be obtained by varying thestereochemistry of the appropriate reagents utilized in the method ofExample 2 above. For instance, by adjusting the reagent used in Step 4of Example 2, compounds such as those of Formulae (II-m) and (II-n) canbe synthesized. Similarly, in Step 6 of Example 2, the regent methyl(1S,3R)-3-aminocyclohexane-1-carboxylate can be used in place of methyl(1R,3R)-3-aminocyclohexane-1-carboxylate to obtain compounds of Formulae(II-b) and (II-e). It will be apparent to the skilled reader that bymaking a combination of these types of modifications to the process setout in Example 2, each of compounds (II-a) to (II-o) depicted above canbe synthesized.

Example 3:(1R,3R)-3-[(7S)-2-[(R)-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (462)

Compositions comprising Compound 462 can be prepared as shown in thescheme below:

Step 1. 6-fluoro-2-methyl-5-nitroquinoline

A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO₃(19.6 mL, 0.437 mol) was stirred for 20 min at 0° C. This was followedby the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) indichloromethane (300 mL) at 0° C. The resulting mixture was stirred for15 h at room temperature (25° C.). The reaction mixture was diluted withwater (300 mL). The pH value of the solution was adjusted to 8 withsodium bicarbonate (saturated aqueous solution). The resulting solutionwas extracted with dichloromethane (3×300 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:4 ethyl acetate/petroleum ether) toafford 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0g, 94%). LCMS (E S , m/z): 207 [M+H]⁺.

Step 2. (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol),chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) intoluene (100 mL) was stirred for 30 min at room temperature (25° C.)under an atmosphere of nitrogen. This was followed by the addition of I₂(410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160mol) in toluene (100 mL). The resulting mixture was stirred for 20 h atroom temperature (25° C.) under hydrogen (50 atm). The resulting mixturewas concentrated under vacuum and purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to afford the crudeproduct (35.0 g). The crude product was dissolved in ethyl acetate (230mL), followed by the addition of D-Camphorsulfonic acid (36.9 g, 0.158mol). The resulting solution was stirred for 1 h at 60° C. and thencooled to room temperature. The solids were collected by filtration, andrinsed with ethyl acetate (120 mL). The solids were dissolved in water(50 mL). The pH value of the solution was adjusted to 8 with sodiumbicarbonate (saturated aqueous solution). The resulting solution wasextracted with ethyl acetate (3×120 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to afford(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a redsolid (25.5 g, 76%). LCMS (ES, m/z): 211 [M+H]⁺.

Step 3. methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline(25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), methylcarbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) wasstirred for 3 h at room temperature (25° C.). The reaction was washedwith 1M hydrogen chloride (2×70 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to afford methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a yellow solid (29.8 g, 92%). LCMS (ES, m/z): 269 [M+H]⁺.

Step 4. methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate(30.5 g, 0.220 mol), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate(25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred for 15 h at 90° C.and then cooled to room temperature. The reaction was quenched by theaddition of water (200 mL) and extracted with ethyl acetate (3×300 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford methyl(2S)-6[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a red oil (32 g, 72%). LCMS (ES, m/z): 406 [M+H]⁺.

Step 5. methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of(2S)-6[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (31.0 g, 76.46 mmol), NH₄Cl (24.3 g, 454.28 mmol), Fe(64.3 g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL), water(100 mL) was stirred for 1 h at 80° C. and then cooled to roomtemperature. The solids were filtered out by filtration. The resultingsolution was diluted with water (300 mL) and extracted with ethylacetate (3×400 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum toafford methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas a dark green solid (27.5 g, 92%). LCMS (ES, m/z): 376 [M+H]⁺.

Step 6. methyl(2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of (R)-2-hydroxy-2-phenylacetic acid (972 mg, 6.39 mmol),HATU (1.20 g, 3.16 mmol), methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(800 mg, 2.13 mmol), DIEA (1.08 mL, 6.20 mmol) in N,N-dimethylformamide(10 mL) was stirred for 5 h at room temperature (25° C.). The resultingsolution was diluted with water (30 mL), and extracted with ethylacetate (3×50 mL). The organic layers were combined and washed withbrine (2×25 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The resultingcrude product was purified by silica gel chromatography (eluting with1:1 ethyl acetate/petroleum ether) to afford methyl(2S)-5((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas a colorless oil (600 mg, 55%). LCMS (ES, m/z): 510 [M+H]⁺

Step 7. methyl(7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

A solution of methyl(2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(600 mg, 1.18 mmol) in glacial acetic acid (5 mL, 98%) was stirred forovernight at 40° C. and then cooled to room temperature. The reactionmixture was diluted with water (10 mL). The pH value of the solution wasadjusted to 8 with sodium bicarbonate (saturated aqueous solution). Theresulting solution was extracted with ethyl acetate (3×15 mL). Theorganic layers were combined and dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford methyl(7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (400 mg, 69%) as a colorless oil. LCMS(ES, m/z): 492 [M+H]⁺.

Step 8.(1R,3R)-3-[(7S)-2-[(R)-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid

A solution of methyl(7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (400 mg, 0.81 mmol), LiOH (100 mg, 4.17mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred forovernight at room temperature (25° C.). The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Column: XBridge Shield RP18 OBD Column, 5 um, 19×150 mm; Mobile Phase,A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (3% to 30% over 21min); Detector: UV 254 nm). The product fractions were lyophilized toafford(1R,3R)-3-[(7S)-2-[(R)-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid as a white solid(83.7 mg, 22%). Enantiomeric excess was determined via HPLC: Column:CHIRALPAK IE-3, Column size: 0.46×5 cm; 3 μm; Mobile phase: Hex (0.1%FA): EtOH=85:15, Flow: 1.0 ml/min. ¹H-NMR (CD₃OD, 400 MHz) δ (ppm):7.47-7.28 (m, 7H), 6.12(s, 1H), 4.84-4.74(m, 2H), 3.79(s, 3H),3.33-3.25(m, 1H), 3.03-2.96 (m, 1H), 2.86-2.82 (m, 1H), 2.38-2.25 (m,2H), 2.25-2.07 (m, 3H), 1.79-1.72 (m, 1H), 1.64-1.57 (m, 2H), 1.40-1.29(m, 2H), 1.16 (d, J=6.8 Hz, 3H). LCMS (ES, m/z): 478 [M+H]⁺; 99.13% ee.

Example 4:(1R,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (452),(1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (515)

Step 1. 2-(difluoromethoxy)-5-fluorobenzaldehyde

A solution of 5-fluoro-2-hydroxybenzaldehyde (2.0 g, 14.3 mmol), diethyl(bromodifluoromethyl)phosphonate (5.69 g, 21.3 mmol), potassiumhydroxide (16.0 g, 285 mmol) in MeCN (100 mL) and water(50 mL) wasstirred for 1 h at −30° C. The reaction mixture was diluted with water(20 mL). The resulting solution was extracted with ethyl acetate (3×100mL) and the organic layers combined and dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The resulting crude product was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford 2-(difluoromethoxy)-5-fluorobenzaldehyde as a yellowsolid (1.46 g, 54%). LCMS (ES, m/z): 191 [M+H]⁺.

Step 2.2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilypoxy]acetonitrile

A solution of 2-(difluoromethoxy)-5-fluorobenzaldehyde (1.46 g, 7.68mmol), TMSCN (760 mg, 7.66 mmol), ZnI₂ (50 mg, 0.16 mmol) indichloromethane (3 mL) was stirred for 2 h at room temperature (25° C.).The resulting mixture was concentrated under vacuum. The resulting crudeproduct was purified by silica gel chromatography (eluting with 1:1ethyl acetate/petroleum ether) to afford2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile as a yellow solid (800 mg, 36%) . LCMS (ES, m/z):290[M+H]⁺.

Step 3. 2[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic Acid

A solution of2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile(800 mg, 2.77 mmol), 1,4-dioxane (2.0 mL), hydrogen chloride (1.0 mL,12M) in water (2 mL) was stirred for 12 h at 70° C. and then cooled toroom temperature. The resulting solution was concentrated under vacuum.The crude product was purified by reverse phase column chromatography(water (containing 0.05% TFA)/MeCN) to afford2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid (400 mg,61%). LCMS (ES, m/z): 237 [M+H]⁺.

Step 4. 6-fluoro-2-methyl-5-nitroquinoline

A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO₃(19.6 mL, 0.437 mol) was stirred for 20 min at 0° C. This was followedby the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) indichloromethane (300 mL) at 0° C. The resulting mixture was stirred for15 h at room temperature (25° C.). The reaction mixture was diluted withwater (300 mL). The pH value of the solution was adjusted to 8 withsodium bicarbonate (saturated aqueous solution). The resulting solutionwas extracted with dichloromethane (3×300 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:4 ethyl acetate/petroleum ether) toafford 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0g, 94%). LCMS (ES, m/z): 207 [M+H]⁺.

Step 5. (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol),chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) intoluene (100 mL) was stirred for 30 min at room temperature (25° C.)under an atmosphere of nitrogen. This was followed by the addition of I₂(410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160mol) in toluene (100 mL). The resulting mixture was stirred for 20 h atroom temperature (25° C.) under hydrogen (50 atm). The resulting mixturewas concentrated under vacuum and purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to afford the crudeproduct (35.0 g). The crude product was dissolved in ethyl acetate (230mL), followed by the addition of D-Camphorsulfonic acid (36.9 g, 0.158mol). The resulting solution was stirred for 1 h at 60° C. and thencooled to room temperature. The solids were collected by filtration, andrinsed with ethyl acetate (120 mL). The solids were dissolved in water(50 mL). The pH value of the solution was adjusted to 8 with sodiumbicarbonate (saturated aqueous solution). The resulting solution wasextracted with ethyl acetate (3×120 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to afford(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a redsolid (25.5 g, 76%). LCMS (ES, m/z): 211 [M+H]⁺.

Step 6. methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline(25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), methylcarbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) wasstirred for 3 h at room temperature (25° C.). The reaction was washedwith 1M hydrogen chloride (2×70 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to afford methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a yellow solid (29.8 g, 92%). LCMS (ES, m/z): 269 [M+H]⁺.

Step 7. methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate(30.5 g, 0.220 mol), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate(25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred for 15 h at 90° C.and then cooled to room temperature. The reaction was quenched by theaddition of water (200 mL) and extracted with ethyl acetate (3×300 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylateas a red oil (32 g, 72%). LCMS (ES, m/z): 406 [M+H]⁺.

Step 8. methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate(31.0 g, 76.46 mmol), NH₄Cl (24.3 g, 454.28 mmol), Fe (64.3 g, 1.15 mol)in tetrahydrofuran (300 mL), ethanol (300 mL), water (100 mL) wasstirred for 1 h at 80° C. and then cooled to room temperature. Thesolids were filtered out by filtration. The resulting solution wasdiluted with water (300 mL) and extracted with ethyl acetate (3×400 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to afford methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline1-carboxylateas a dark green solid (27.5 g, 92%). LCMS (ES, m/z): 376 [M+H]⁺.

Step 9. methyl(2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(200 mg, 0.53 mmol),2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid (220 mg,0.93 mmol), DMTMM (350 mg, 1.26 mmol) in dichloromethane (5 mL) wasstirred for 1 h room temperature (25° C.). The resulting solution wasconcentrated under vacuum. The resulting crude product was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford methyl(2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateas a yellow solid (70.0 mg, 22%). LCMS (ES, m/z): 594 [M+H]⁺.

Step 10. methyl(7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

A solution of methyl(2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(70.0 mg, 0.12 mmol) in glacial acetic acid (2.0 mL) was stirred forovernight at 40° C. and then cooled to room temperature. The resultingsolution was concentrated under vacuum. The resulting crude product waspurified by silica gel chromatography (eluting with 1:2 ethylacetate/petroleum ether) to afford methyl(7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylateas a yellow solid (50.0 mg, 74%). LCMS (ES, m/z): 576 [M+H]⁺.

Step 11.(1R,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid;(1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicAcid

A solution of methyl(7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline -6-carboxylate (50.0 mg, 0.09 mmol), LiOH (10.0 mg,0.42 mmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was stirredfor overnight at room temperature (25° C.). The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Column, XBridge Shield RP18 OBD Column, 30×150 mm, 5 um; Mobile phase,A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (25.0% to 35.0% over8 min); Detector, UV 254/220 nm). The product fractions wereconcentrated to afford(1R,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7 -methyl-3H,6H,7 H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (452) as a whitesolid (4.50 mg, 9%), and(1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylicacid (515) as a white solid (4.30 mg, 9%). Enantiomeric excess wasdetermined via HPLC: Column: CHIRALPAK IE-3, Column size: 0.46×5 cm; 3μm; Co-Solvent: IPA (20 mM NH₃) Gradient (B%) : 10% to 50% in 4.0 min,hold 2.0 min at 50%.

First eluting isomer (452): ¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 7.63-7.61(m, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.41(d, J=9.2Hz, 1H) 7.20-7.13 (m, 2H),6.67-6.30 (m, 2H), 4.98-4.95 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H),3.15-2.86 (m, 3H), 2.46-2.20 (m, 5H), 1.81-1.53 (m, 5H), 1.13 (d, J=6.8Hz, 3H). LCMS (ES, m/z): 562 [M+H]⁺.Second eluting isomer (515): ¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 7.55-7.53(m, 1H), 7.47-7.42 (m, 2H), 7.40-7.12 (m, 2H), 6.85-6.44 (m, 2H),4.94-4.91 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.22-2.84 (m, 3H),2.46-2.23 (m, 5H), 1.84-1.61 (m, 5H), 1.14 (d, J=6.4 Hz, 3H). LCMS (ES,m/z): 562 [M+H]⁺; >99.99% ee.

In some embodiments, the disclosure provides the first eluting isomerobtained from Step 11 of the process described in Example 4. In someembodiments, the disclosure provides the second eluting isomer obtainedfrom Step 11 of the process described in Example 4.

Example 5: HTRF Biochemical Assay for CBP and BRD4 Activity

The ability of compounds of formula I to selectively inhibit CBP wasdetermined using the following HTRF biochemical assay for CBP and BRD4activity. The assay was performed in a final volume of 6 μL in assaybuffer containing 50 mM Hepes (pH 7.5, (0.5M Hepes, pH 7.5 solution;Teknova H1575)), 0.5 mM GSH, 0.01% BGG (0.22 μM filtered, Sigma,G7516-25G), 0.005% BSA (0.22 μM filtered, EMD Millipore Cosporation,126575) and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantitiesof 10-point, 3-fold serial dilution in DMSO were pre-dispensed into 1536assay plates (Corning, #3724BC) for a final test concentration of 33 μMto 1.7 nM, top to lowest dose, respectively. 3 μL of 2× Protein and 3 μLof 2× Peptide Ligand were added to assay plates (pre-stamped withcompound). Plates were incubated for varying times at room temperatureprior to measuring the signal. TR-FRET (Time-Resolved FluorescenceResonance Energy Transfer) was measured on a PHERAstar plate reader(BMG, equipped with HTRF optic module [337/520/490]) or on an Envisionplate reader (PerkinElmer, equipped with the TRF Laser unit, TRF dualmirror D400/D505 and emission filters M520 and M495). Data were reportedas percent inhibition compared with control wells based on the followingequation: % inh=1−((TR-FRET ratio−AveLow)/(AveHigh−AveLow)) whereTR-FRET ratio=(Fluorescence at 520 nm/Fluorescence at 490nm)*10000),AveLow=average TR-FRET ratio of no enzyme control (n=32), andAveHigh=average TR-FRET ratio of DMSO control (n=32). IC50 values weredetermined by curve fitting of the standard 4 parameter logistic fittingalgorithm included in the Activity Base software package: IDBS XEDesigner Model205. Data is fitted using the Levenburg Marquardtalgorithm. For all assay formats data were reported as percentinhibition compared with control wells based on the following equation:% inh=100*((FLU−AveLow)/(AveHigh−AveLow)) where FLU=measuredFluorescence, AveLow=average Fluorescence of no enzyme control (n=32),and AveHigh=average Fluorescence of DMSO control (n=32). IC50 valueswere determined by curve fitting of the standard 4 parameter logisticfitting algorithm included in the Activity Base software package: IDBSXE Designer Model205. Data is fitted using the Levenburg Marquardtalgorithm. IC₅₀ values are shown in FIG. 1. As set forth in FIG. 1, anIC₅₀ value of less than or equal to 0.01 μM is marked “++++”; a valuegreater than 0.01 μM and less than or equal to 0.1 μM is marked “+++”; avalue greater than 0.1 μM and less than or equal to 1 μM is marked “++”;and values greater than 1μM is marked “+.” Compounds that were nottested in a particular assay are marked “NT.”

In some embodiments, the CBP Inhibitor Comound is also selective for CBPactivity compared to BRD4 activity, as determined by obtaining a IC₅₀value for CBP inhibition in the HTRF biochemical assay for CBP that islower than the corresponding IC50 value obtained for the HTRFbiochemical assay for BRD4 activity according to Example 5. A CBPInhibitor Composition can contain an amount of a compound of thedisclosure, or a pharmaceutically acceptable salt thereof, and amountsof one or more stereoisomers of the compound up to amounts that retainsufficient activity of the composition with respect to CBP inhibitionand selectivity for CBP over BRD4. Using the methods provided herein,CBP Inhibitor Compositions can contain 95% by HPLC or more of a compoundof the disclosure, or a pharmaceutically acceptable salt thereof, and upto 5% by HPLC of one or more stereoisomers of the compound.

In a preferred embodiment, the present disclosure relates to compound424 having an IC₅₀ value of less than or equal to 0.01 μM for theinhibition of CBP, and an IC₅₀ value of greater than 0.1 μM and lessthan or equal to 1 μM for the inhibition of BRD4 as determined by theHTRF biochemical assay for CBP and BRD4 activity described herein inExample 5.

In some embodiments, the present disclosure relates to a compound ofFormula (II) selected from the group consisting of compound 424 and itsrelated stereoisomers of structures (II-a) to (II-o) depicted above,having an IC₅₀ value of less than or equal to 0.01 μM for the inhibitionof CBP, and an IC₅₀ value of greater than 0.1 μM and less than or equalto 1 μM for the inhibition of BRD4 as determined by the HTRF biochemicalassay for CBP and BRD4 activity described herein in Example 5.

Further embodiments of the disclosure are set out in the followingnumbered clauses:

1. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein,

R¹ is —OR⁵;

R⁵ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶ is —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl,aryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,or aryl is optionally substituted with one or more —R¹⁰;

R^(6′) is H or —C₁-C₆alkyl;

R⁷ is —H, halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)2C₁-C₆alkyl, —S(O)₂OH, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OH, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂,—S(O)₂NH₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl) or tetrazole;

R¹⁰ is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—OC₃-C₆cyclo alkyl, —Oaryl, —Ohetero aryl, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂C₁-C₆alkyl, —C(O)C₁ -C₆alkyl, —C(O)NH₂, —C(O)NH(C₁ -C₆alkyl),—NHC(O)C₁ -C₆alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SOC₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²;

R¹² is independently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,-C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁ -C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S (O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl);

m is an integer from 0 to 5, and q is an integer from 0 to 4.

2. The compound of clause 1, wherein R¹² is halogen.

3. The compound of any one of clauses 1-2, wherein m is 3.

4. The compound of any one of clauses 1-3, wherein R^(6′) is H.

5. The compound of any one of clauses 1-4, wherein R⁶ is aryl.

6. The compound of any one of clauses 1-5, wherein R⁷ is —C(O)OH.

7. The compound of any one of clauses 1-6, wherein R⁵ is methyl.

8. The compound of clause 1, wherein the compound is of formula (III-c):

or a pharmaceutically acceptable salt thereof, wherein R⁵ is—C₁-C₆alkyl; and R⁶ is phenyl optionally substituted with one or moreR¹⁰.9. The compound of clause 1, wherein the compound is of formula (III-d):

or a pharmaceutically acceptable salt thereof, wherein:

R⁵ is —C₁-C₃alkyl;

R⁶ is phenyl optionally substituted with one or more R¹⁰;

R¹⁰ is independently, at each occurrence halogen, —OC₁-C₆alkyl,—OC₃-C₆cycloalkyl, —Oaryl, or —Oheteroaryl, wherein each alkyl,cycloalkyl, aryl or heteroaryl is optionally substituted with one ormore —R¹²; and R¹² is halogen.

10. The compound of any one of clauses 1-7, wherein R⁶ is aryloptionally substituted with one or more R¹⁰.

11. The compound of any one of clauses 1-7, wherein R⁶ is phenyloptionally substituted with one or more R¹⁰.

12. The compound of any one of clauses 1-6, 8 or 10-11, wherein R⁵ is—C₁-C₃alkyl.

13. The compound of any one of clauses 1-6 or 8-12, wherein R⁵ ismethyl.

14. The compound of any one of clauses 1-13, wherein R¹⁰ isindependently, at each occurrence, halogen or —OC₁-C₆alkyl, wherein—OC₁-C₆alkyl is optionally substituted with halogen.

15. A pharmaceutical composition comprising a compound of any one ofclauses 1-14 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is —OR⁵; R⁵is —C₁-C₆alkyl; R⁶ is —C₁-C₆alkyl, —C₃-C₈cycloalkyl, or a 5-6 memberedheteroaryl, wherein each alkyl, cycloalkyl, heteroaryl is optionallysubstituted with one or more R¹⁰; R¹⁰ is each independently, at eachoccurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,—C₄-C₈cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo,—NO₂, —CN, —NH₂, —OC₁-C₆alkyl, —OC₃-C₆cycloalkyl, —Oaryl, —Oheteroaryl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl), wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl isoptionally substituted with one or more —R¹²; or wherein any two R¹⁰when on non-adjacent atoms, can combine to form a bridging cycloalkyl orheterocyclyl; or wherein any two R¹⁰ when on adjacent atoms, can combineto form a cycloalkyl, heterocyclyl, aryl or heteroaryl; and R¹² isindependently, at each occurrence, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₄-C₈cycloalkenyl, heterocyclyl,heteroaryl, aryl, —OH, halogen, oxo, —NO₂, —CN, —NH₂, —OC₁-C₆alkyl,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)OC₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl),—S(O)N(C₁-C₆alkyl)₂, or—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl).
 2. The compound of claim 1, wherein R⁵is methyl.
 3. The compound of claim 2, wherein R⁶ is —C₁-C₆alkyl,wherein the alkyl is optionally substituted with one or more R¹⁰.
 4. Thecompound of claim 3, wherein R⁶ is methyl.
 5. The compound of claim 3,wherein R¹⁰ is selected from —C₃-C₈cycloalkyl, aryl, and heteroaryl,wherein each cycloalkyl, aryl, or heteroaryl is optionally substitutedwith one or more —R¹².
 6. The compound of claim 5, wherein R¹⁰ isselected from cyclopentyl, cyclohexyl, phenyl, and pyrazolyl, whereineach cycpentyl, cyclohexyl, phenyl, or pyrazolyl is optionallysubstituted with one or more —R¹².
 7. The compound of claim 5, whereineach R¹² is independently selected from halogen.
 8. The compound ofclaim 7, wherein each R¹² is independently selected from F and Cl. 9.The compound of claim 7, selected from the group consisting of:


10. The compound of claim 2, wherein R⁶ is —C₃-C₈cycloalkyl, wherein thecycloalkyl is optionally substituted with one or more R¹⁰.
 11. Thecompound of claim 10, wherein R⁶ is selected from cyclopentyl,cyclohexyl, and cycloheptyl, each of which is optionally substitutedwith one or more R¹⁰.
 12. The compound of claim 10, wherein each R¹⁰ isindependently selected from halogen.
 13. The compound of claim 12,wherein each R¹⁰ is F.
 14. The compound of claim 12, wherein thecompound is selected from the group consisting of:


15. The compound of claim 2, wherein R⁶ is a 5-6 membered heteroaryl,wherein the heteroaryl is optionally substituted with one or more R¹⁰.16. The compound of claim 15, wherein R⁶ is pyridinyl optionallysubstituted with one or more R¹⁰.
 17. The compound of claim 15, whereineach R¹⁰ is independently selected from halogen, or wherein any two R¹⁰when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl,aryl or heteroaryl.
 18. The compound of claim 17, wherein each R¹⁰ isCl, or wherein any two R¹⁰ when on adjacent atoms, can combine to form acycloalkyl, heterocyclyl, aryl or heteroaryl.
 19. The compound of claim17, selected from the group consisting of:


20. A compound, selected from the group consisting of:


21. A pharmaceutical composition comprising the compound of claim 1, ora pharmaceutically acceptable salt thereof.